Dibenz(b,f)oxepin derivatives

ABSTRACT

Dibenz[b,f]oxepins of the formula ##STR1## wherein R, R 1 , R 2 , R 3  and R 4  are as hereinafter described, are described. The foregoing compounds exhibit strong central depressant and neuroleptic properties, and are useful, for example, in the treatment of acute or chronic schizophrenia and also as tranquilizers.

This is a division of application Ser. No. 534,033 filed Dec. 18, 1974,now U.S. Pat. No. 4,032,525, issued June 28, 1977.

BRIEF SUMMARY OF THE INVENTION

The dibenz[b,f]oxepin derivatives of the invention are compounds of theformula ##STR2## wherein R is lower alkyl, lower alkenylalkyl, loweralkynylalkyl, which may be substituted by cyano, hydroxy or alkanoyloxy,when other than methyl, or a group of the formula ##STR3## WHEREIN X isoxygen, sulfur, imino, lower alkylimino or methylene, Y is ethylene orpropylene which may be substituted by lower alkyl and m is 0 or 1; oneof R₁ and R₂ is hydrogen and the other is halogen, lower alkyl, loweralkoxy, lower alkylthio, trifluoromethyl or hydroxy; and one of R₃ andR₄ is hydrogen and the other is hydrogen, halogen, lower alkyl, loweralkoxy, lower alkylthio, trifluoromethyl or hydroxy,

Or pharmaceutically acceptable acid addition salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The dibenz[b,f]oxepin derivatives of the invention are compounds of theformula ##STR4## wherein R is lower alkyl, lower alkenyl, lower alkynyl,cyano-lower alkyl of 3-7 carbon atoms, hydroxy-lower alkyl of 2-6 carbonatoms, alkanoyloxy-lower alkyl with 2-6 carbon atoms in the lower alkylmoiety, cyano-lower alkenyl alkyl, hydroxy-lower alkenyl-alkyl,alkanoyloxy-lower alkenyl-alkyl, cyano-lower alkynyl-alkyl,hydroxy-lower alkynyl-alkyl, alkanoyloxy-lower alkynyl-alkyl, or R is agroup of the formula ##STR5## wherein X is oxygen, sulfur, imino, loweralkylimino or methylene, Y is ethylene or propylene which may besubstituted by lower alkyl and m is 0 or 1; one of R₁ and R₂ is hydrogenand the other is halogen, lower alkyl, lower alkoxy, lower alkylthio,trifluoromethyl or hydroxy; and one of R₃ and R₄ is hydrogen and theother is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio,trifluoromethyl or hydroxy,

or pharmaceutically acceptable acid addition salts thereof.

As used herein, the term "lower alkyl," alone or in combination withother groups, denotes straight-chain or branched-chain aliphatic groupswhich, unless otherwise described, preferably contain from 1 to 6 carbonatoms, for example, methyl, ethyl, isopropyl, n-hexyl and the like. Theterm "lower alkoxy" denotes an alkyl ether group in which the loweralkyl group is as described above, for example, methoxy, ethoxy,propoxy, pentoxy, and the like. The terms "lower alkenyl alkyl" and"lower alkynyl alkyl" mean that the lower alkenyl and lower alkynyl areeach linked via an alkyl (alkylene) group, i.e., at least via a methyl(methylene) and denote straight-chain or branched-chain groups andpreferably contain from 3 to 6 carbon atoms, for example, allyl,2-butenyl or 2,4-pentadienyl and 2-propynyl or 2-butynyl. The term"alkanoyloxy" denotes a straight-chain or branched-chain group whichcontains from 2 to 18 carbon atoms, for example, acetoxy, pivaloyloxy,n-pentanoyloxy, and the like. Preferred alkanoyloxy groups are thosewhich contain from 6 to 18 carbon atoms, for example, hexanoyloxy,heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy,dodecanoyloxy, tetradecanoyloxy, hexadecanoyloxy, octadecanoyloxy, andthe like. The term "halogen" denotes fluorine, chlorine, bromine andiodine; chlorine is preferred.

The dibenz[b,f]oxepin derivatives of the invention, that is, thecompounds of formula I and their pharmaceutically acceptable acidaddition salts exhibit strong central depressant and neurolepticproperties, and can be used, for example, in the treatment of acute orchronic schizophrenia and also as tranquilizers. Advantageously, incertain derivatives of the invention, cataleptic side-effects areobserved only to slight extent, i.e., only insignificant motor disordersoccur. More particularly, this advantage is present in those compoundsof formula I in which R is cyanoethyl or a group of formula (a),especially the group of the formula ##STR6## and their pharmaceuticallyacceptable acid addition salts. Such derivatives are thereforepreferred. Especially preferred derivatives are3-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propionicacid nitrile,3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone,3-[2-{4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinoneand3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinoneand their pharmaceutically acceptable acid addition salts.

The dibenz[b,f]oxepin derivatives, that is, the compounds of formula Iof the invention and their salts, can be prepared by the followingprocesses:

(a) reacting a compound of the formula ##STR7## wherein Z is a leavingatom or group and R₁ '-R₄ ' have the values accorded to R₁ -R₄hereinbefore but wherein any hydroxy group(s) present can be protected.

with a compound of the formula ##STR8## wherein R is as earlierdescribed,

(b) reducing a compound of the formula ##STR9## wherein R and R₁ '-R₄ 'are as earlier described, or

(c) reacting a compound of the formula ##STR10## wherein R₁ '-R₄ ' areas earlier described, with a compound yielding the group R,

or

(d) for the preparation of a compound of formula I wherein R isalkanoyloxy-lower alkyl, alkanoyloxy-lower alkenyl alkyl oralkanoyloxy-lower alkynyl alkyl, reacting a compound of the formula##STR11## wherein R₁ '-R₄ ' is as earlier described and R' ishydroxy-lower alkyl, hydroxy-lower alkenyl alkyl or hydroxy-loweralkynyl alkyl,

with an alkanecarboxylic acid or a reactive derivative thereof,

or

(e) for the preparation of a compound of formula I wherein R is loweralkyl or hydroxy-lower alkyl, reducing a compound of the formula##STR12## wherein R₁ '-R₄ ' are as earlier described and R₅ is loweralkanoyl, hydroxy-lower alkanoyl or lower alkoxycarbonyl,

and converting any protected hydroxy group(s) denoted by R₁ '-R₄ ' intohydroxy group(s) if necessary and, if desired, converting a productobtained into a pharmaceutically acceptable acid addition salt.

The leaving atom or group denoted by Z in the starting materials offormula II is preferably halogen or alkyl-substituted oraryl-substituted sulfonyloxy. The alkyl group present in the leavinggroup is preferably lower alkyl, especially methyl, the aryl grouppresent in the leaving group is preferably phenyl or tolyl. When Z ishalogen, chlorine or bromine is preferred.

The starting materials of formula II can be prepared according to knownmethods. For example, the starting materials of formula II wherein Z isas earlier described, can be prepared as follows:

When Z is halogen, a corresponding 10-oxo compound is converted byreduction, for example, using sodium borohydride, into the 10-hydroxycompound which is then reacted with a suitable halide, for example,thionyl chloride or thionyl bromide, or with a hydrohalide in thepresence of a water-binding agent, for example, hydrogen chloride andcalcium chloride.

When Z is alkyl-substituted or aryl-substituted sulfonyloxy, acorresponding 10-hydroxy compound is reacted with an alkyl-substitutedor aryl-substituted sulfonic acid halide, for example, the chloride.

The starting materials of formula III can be prepared, for example, asset forth below, wherein Z and R are as previously described and R₆ is asuitable protecting group, for example, benzyl or lower alkoxycarbonyl,such as, methoxycarbonyl or ethoxycarbonyl.

More particularly, the compounds of formula III are prepared by thecondensation of a compound of the formula ##STR13## with a compound ofthe formula

    Z--R                                                       IX

which is preferably carried out in the presence of an acid-bindingagent, for example, potassium carbonate or triethylamine. The protectinggroup denoted by R₆ is subsequently removed from the condensationproduct of the formula ##STR14## and yields the compound ##STR15## Thebenzyl group can be removed by hydrogenolysis and a lower alkoxycarbonylgroup can be removed, for example, by alkaline hydrolysis.

The reaction of a compound of formula II with a compound of formula IIIin accordance with process embodiment (a) can be carried out in theabsence of a solvent. If, however, the reaction is carried out in thepresence of a solvent, the solvent is conveniently an organic solventsuch as an aromatic hydrocarbon, for example, benzene or toluene, alower alkanol, for example, methanol or ethanol, a chlorinatedhydrocarbon, for example, methylene chloride, trichloroethylene,chloroform, carbon tetrachloride or chlorobenzene, an aliphatic orcyclic ether, for example, diethyl ether, tetrahydrofuran or dioxane,dimethylformamide or dimethylsulfoxide. The reaction is convenientlycarried out at a temperature in the range of from about 30° C. to about200° C., preferably at a temperature in the range of from about 60° C.to about 150° C. The reaction is advantageously carried out in thepresence of an acid-binding agent, for example, in the presence of analkali carbonate, such as potassium carbonate, or in the presence of anexcess of the starting material of formula III.

The enamine starting materials of formula IV can be prepared by reactinga corresponding 10-oxo compound with a compound of formula III. Thisreaction can be carried out, for example, in the presence of a strongacidic agent in an aromatic solvent with heating, for example, at atemperature in the range of from about 80° C. to about 150° C. Examplesof acidic agents which can be used are mineral acids such asmethanesulfonic acid, p-toluenesulfonic acid, or the like. The preferredaromatic solvents are benzene, toluene, and o-, m- or p-xylene. Duringthe heating there is formed an azeotrope between the solvent and thewater formed in the reaction, which can be removed by distillation. Thewater formed can also be removed by the addition of a dehydrating agentsuch as titanium tetrachloride.

An obtained enamine alcohol of formula IV, that is, a compound offormula IV wherein R is hydroxy, can be converted into the correspondingester of formula IV, preferably by reaction with the correspondingalkanecarboxylic acid in the presence of a non-acidic dehydrating agent,for example, dicyclohexylcarbodiimide, carbonyldiimidazole, or the like.

The reduction of an enamine of formula IV in accordance with processembodiment (b) is preferably carried out by treatment with an alkalimetal borohydride in the presence of a strong acid. Sodium borohydrideor potassium borohydride, particularly sodium borohydride, is preferablyused as the alkali metal borohydride. However, lithium borohydride canalso be used. The strong acid can be either an organic acid or aninorganic acid. Suitable organic acids comprise straight-chain orbranched-chain, lower mono- or dicarboxylic acids which contain up to 4carbon atoms and which may be halogen-substituted, for example, formicacid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionicacid, isobutyric acid, oxalic acid and the like. Acetic acid and oxalicacid are preferred. Suitable inorganic acids comprise, in particular,sulfuric acid, hydrohalic acids, especially hydrochloric acid, and thelike. A preferred inorganic acid is concentrated sulfuric acid. Sincethe enamines of formula IV are unstable in the presence of water, thereduction is conveniently carried out in the absence of water.Therefore, preferably only anhydrous acids or only those acids which, ifthey contain some water, do not release water, for example, concentratedsulfuric acid, are used. The reduction with an alkali metal borohydrideand a strong acid is advantageously carried out in an ether such asdiethyl ether, tetrahydrofuran, dioxane, diethyleneglycol dimethyl ether(diglyme) or dimethoxyethane, at a temperature in the range of fromabout room temperature and the reflux temperature of the mixture. Thereduction is preferably carried out under reflux conditions. Thereduction of an enamine of formula IV can also be carried out by othermethods, for example, by treatment with formic acid or zinc and glacialacetic acid. The latter reductions are also preferably carried out at atemperature in the range of from about room temperature to the refluxtemperature of the mixture, preferably at the reflux temperature.

The starting materials of formula V can be prepared, for example, byreacting a compound of formula II with a mono-N-protected piperazinesuch as N-carbethoxypiperazine. The reaction product is subsequentlysubjected to an alkaline saponification, for example, using aqueousalkali.

The compounds yielding the group R which are reacted with the startingmaterials of formula V can be, for example, the compounds of formula IX.On the other hand, there may also be used the corresponding alkenesyielding the group R which, with the uptake of a hydrogen atom andsaturation of a double bond, can be reacted with a starting material offormula V to give the desired compound of formula I. Other compoundsyielding the group R are the corresponding cyclic ethers, these lead tocompounds of formula I wherein R is hydroxyalkyl. Examples of suchcyclic ethers are oxirane, methyloxirane, oxetane and tetrahydrofuran.

Compounds of formula IX wherein R is a group of formula (a), namelycompounds of the formula ##STR16## wherein X, Y, Z and m are as earlierdescribed, can be obtained, for example, by converting a lactam of theformula ##STR17## wherein X and m are as earlier described, into acorresponding alkali metal salt, for example, the sodium salt. Thisconversion can be carried out, for instance, by treating a lactam offormula XII with an alkali metal, an alkali metal hydride or an alkalimetal amide in an aromatic hydrocarbon, for example, benzene or toluene,or dimethylformamide. The resulting alkali metal salt is subsequentlyreacted with a compound of the formula

    R.sub.7 O--Y--Hal                                          XIII

wherein Y is as earlier described, Hal is halogen and R₇ is a suitableprotecting group, for example, benzyl or 2-tetrahydropyranyl.

The protecting group denoted by R₇ in the reaction product is thencleaved hydrogenolytically, when R₇ is benzyl, or hydrolytically, whenR₇ is 2-tetrahydropyranyl. The resulting hydroxy compound is treatedwith a halogenating agent, for example, thionyl chloride, or with analkyl-substituted or aryl-substituted sulfonic acid halide, for example,the chloride, to give a starting material of formula XI.

The alkenes corresponding to the compounds of formula XI are obtained byreplacing the compounds of formula XIII with a corresponding alkene ofthe formula

    Y'--Hal                                                    XIV

wherein Hal is as previously described and Y' is an olefinic groupcontaining one hydrogen atom less than Y as earlier described.

An alkanoyl ester yielding the group R which may be used in processembodiment (c) can be prepared from a corresponding hydroxy-lower alkyl,hydroxy-lower alkenyl alkyl or hydroxy-lower alkynyl alkyl compound byreaction, with a corresponding alkanecarboxylic acid halide.

The reaction of a starting material of formula V with a compoundyielding the group R in accordance with process embodiment (c) isconveniently carried out in an inert organic solvent, for example, anaromatic hydrocarbon such as benzene or toluene, a chlorinatedhydrocarbon such as chloroform, an ether such as dioxane ordimethoxyethane, a lower alkanol such as methanol, ethanol or butanol, aketone such as acetone or methyl ethyl ketone, dimethylformamide ordimethylsulfoxide. The reaction is preferably carried out at atemperature in the range of from about room temperature and the boilingpoint of the reaction mixture. When a compound of formula IX is used,the reaction is preferably carried out in the presence of anacid-binding agent; for example, in the presence of an alkali metalcarbonate such as sodium carbonate or potassium carbonate, or in thepresence of an inert organic base such as triethylamine. An excess ofthe base of formula V can also be used as the acid-binding agent.

The esterification of a starting material of formula VI in accordancewith process embodiment (d) is conveniently carried out by treatment atroom temperature to about 150° C., e.g. by heating to a temperature inthe range of from about 50° to about 150° C., with a reactive derivativeof the appropriate alkanecarboxylic acid, for example, the acid chlorideor acid anhydride. The esterification can also be carried out byreaction with an alkanecarboxylic acid in the presence of a strongacidic catalyst such as sulfuric acid or p-toluenesulfonic acid, or inthe presence of a dehydrating agent such as dicyclohexylcarbodiimide orcarbonyldiimidazole. The esterification is preferably carried out in anorganic solvent, for example, benzene, toluene or pyridine.

The starting materials of formula VII can be prepared, for example, byreacting a compound of formula II with a piperazine derivative of theformula ##STR18## wherein R₅ is lower alkanoyl, hydroxy-lower alkanoylor lower alkoxycarbonyl.

The lower alkanoyl denoted by R₅ in formulas XV and VII isstraight-chain or branched-chain group derived from alkanecarboxylicacid containing at least two carbon atoms, preferably with a maximum of6 carbon atoms, such as acetyl, propionyl, isobutyryl or n-hexanoyl. Thehydroxy-lower alkanoyl groups have an analogous significance. The loweralkoxycarbonyl denoted by R₅ preferably contains 2 to 6, most preferably2 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl orisopropoxycarbonyl.

The preparation of the starting materials of formula VII from thecompounds of formulas II and XV is carried out in essentially the samemanner and under the same conditions as described hereinbefore for thereaction of a compound of formula II with a compound of formula III.

The reduction of a starting material of formula VII in accordance withprocess embodiment (e) is preferably carried out using a complexaluminum hydride, for example, an alkali metal aluminum hydride such aslithium aluminum hydride, sodium aluminum hydride or potassium aluminumhydride or, preferably, an alkali metaldihydro-bis(2-methoxyethoxy)-aluminate such as sodiumdihydrobis(2-methoxyethoxy)-aluminate. The reduction is preferablycarried out in an inert organic solvent, for example, benzene,tetrahydrofuran or diethyl ether. The temperature at which thisreduction is carried out is not critical, but the reduction isconveniently carried out at a temperature in the range of from aboutroom temperature to the boiling point of the mixture.

When it is desired to prepare a compound of formula I wherein R₁ -R₄ ishydroxy, there is preferably used a starting material of formula II, IV,V, VI or VII in which the corresponding hydroxy group is protected, forexample, by a lower alkyl or benzyl group. After carrying out therespective embodiment of the process using such a starting material, theprotecting group is cleaved, preferably by treatment with a borontrihalide, for example, boron tribromide or boron trichloride, in ananhydrous inert solvent, for example, benzene, toluene or xylene, or ahalogenated hydrocarbon such as methylene chloride, chloroform or carbontetrachloride. The cleavage of the protecting group is preferablycarried out at a low temperature, for example, at a temperature in therange of from about -70° C. to room temperature.

The bases of formula I form acid addition salts with pharmaceuticallyacceptable inorganic acids, for example, with hydrohalic acids such ashydrochloric acid, hydrobromic acid or hydroiodic acid, or with othermineral acids such as sulfuric acid, phosphoric acid, nitric acid, orthe like, and with organic acids, for example, tartaric acid, citricacid, camphor-sulfonic acid, methanesulfonic acid, toluenesulfonic acid,salicyclic acid, ascorbic acid, maleic acid, mandelic acid or the like.The preferred salts are the hydrohalides, especially the hydrochlorides,the maleates and the methanesulfonates. The pharmaceutically acceptableacid addition salts are preferably prepared in a suitable solvent, forexample, ethanol, acetone or acetonitrile, by treating the free basewith an appropriate nonaqueous acid. Depending on the molar ratio of thefree base to acid, there is obtained, because of the two nitrogen atomson the piperazine group, a salt containing one or two mols of acid permol of base, that is, a mono or di salt. In the working-up of a di saltthat is obtained, the corresponding di or mono salt is obtaineddepending on the solubility of the mono or di salt in the solvent used.

The bases of formula I are partly crystalline, solid substances whichhave a relatively good solubility in dimethylsulfoxide,dimethylformamide, chlorinated hydrocarbons such as chloroform ormethylene chloride, aromatic hydrocarbons such as benzene or toluene,and in alkanols such as methanol or ethanol and which are relativelyinsoluble in water.

The pharmaceutically acceptable acid addition salts of the bases offormula I are crystalline, solid substances. They have a relatively goodsolubility in dimethylsulfoxide, dimethylformamide or alkanols such asmethanol or ethanol. The salts are also partially soluble in chloroform,methylene chloride or water, and relatively insoluble in benzene, etheror petroleum ether.

In order to demonstrate the advantageous pharmacological activity of thedibenz[b,f]oxepin derivatives of formula I of the invention, thefollowing representative derivatives, test compounds, were tested:

    ______________________________________                                        Derivative A:                                                                 1-[10,11-Dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-                     methyl-piperazine dihydrochloride.                                            Derivative B:                                                                 3-{4-[2-Chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-                      piperazinyl} -1-propanol dihydrochloride.                                     Derivative C:                                                                 3-[2-{4-[2,8-Dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-                     yl]-1-piperazinyl}-ethyl]-2-oxazolidinone dihydrochloride.                    Derivative D:                                                                 3-[2-{4-[10,11-Dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-                     yl]-1-piperazinyl}-ethyl]-2-oxazolidinone dihydrochloride.                    Derivative E:                                                                 3-[2-{4-[2-Chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin                    10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone maleate.                         Derivative F:                                                                 3-[2-{4-[8-Fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin                    10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone dihydrochloride.                 Derivative G:                                                                 3-[2-{4-[2-Chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-                     1-piperazinyl}-ethyl]-2-oxazolidinone maleate.                                Derivative H:                                                                 3-{4-[2-Chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-                      piperazinyl}-propionic acid nitrile.                                            Chlorpromazine, a recognized central depressant or                          neuroleptic agent was used as the standard.                                   ______________________________________                                    

The central depressant or neuroleptic properties of the test substancewere determined numerically by way of the following two tests: I)determination of homovanillic acid and II) the "Pole Climbing" test.

I. Determination of Homovanillic Acid

Rats are injected with the derivative to be tested two hours before theyare killed. Homovanillic acid is extracted from the supernatant of thebrain homogenate into butyl acetate and later into an aqueous solution,and oxidized with potassium ferricyanide to a fluorescent dimer. Fromthe increased concentration of homovanillic acid (HVA) it can beconcluded that the derivative under investigation acts likechlorpromazine, i.e., it increases the turnover of dopamine in the basicganglia. The homovanillic acid titre in untreated rats is arbitrarilyfixed at 100%.

    ______________________________________                                        RESULTS:                                                                      Derivative Dose mg/kg. p.o.                                                                            Increase in HVA, %                                   ______________________________________                                        A          2             235                                                  B          3.5           260                                                  C          5             365                                                  D          15            335                                                  E          10            260                                                  F          50            265                                                  G          50            225                                                  H          50            275                                                  Chlorpromazine                                                                           20            320                                                  ______________________________________                                    

In this test, derivatives A-E show an activity which, on a dose basis,exceeds that of chlorpromazine, while the activity of derivatives F-Halmost approaches that of chlorpromazine.

II. "Pole Climbing" Test

This test provides information about behavior reactions of rats. Ratsare trained to avoid, by climbing up a vertical pole in the testchamber, an electrical impulse -- unconditioned impulse -- released viathe wire-latticed floor some seconds after an acoustic signal --conditioned impulse.

The blocking of the conditioned reaction is designated by the parameterED₅₀ (mg/kg. p.o.) and the blocking of the unconditioned reaction isdesignated by the parameter ED₁₀ (mg/kg. p.o.).

The parameter ED₅₀ -- blocking of the conditioned reaction -- provides ameasure of the strength of the neuroleptic activity of the derivativeunder investigation. The quotient ED₁₀ -- blocking of the unconditionedreaction -- ED₅₀ -- blocking of the conditioned reaction -- provides ameasure of the quality of activity of the derivative under investigationsince, when the quotient increases, a greater selectivity of theneuroleptic activity, that is, slighter neurotoxic side-effects, ispresent.

    ______________________________________                                        RESULTS:                                                                                ED.sub.50 (blocking of                                                                     Quotient ED.sub.10 (blocking of                                  the conditioned                                                                            the unconditioned reaction)/                                     reaction)    ED.sub.50 (blocking of the                             Derivative                                                                              mg/kg.p.o.   conditioned reaction)                                  ______________________________________                                        A         3.2          3.1                                                    D         7.6          5.6                                                    E         3.5          2.8                                                    F         7.0          5.1                                                    G         15.5         3.5                                                    H         14.0         >21                                                    Chlorpromazine                                                                          11.8         2.5                                                    ______________________________________                                    

In this test, derivatives A-F exhibit a neuroleptic strength of actionwhich exceeds that of chorpromazine, while the strength of action ofderivatives G and H is somewhat lower than that of chlorpromazine. Thequality (selectivity) of the neuroleptic activity is, however, superiorin all of derivatives A-H to that of chlorpromazine; in the case ofderivative H this superiority is particularly evident.

In order to demonstrate the lack of any significant catalepticside-effects, the following test was carried out:

III. Catalepsy Test

A cataleptic activity -- "wax rigidity," i.e., abnormally long retentionof a fixed body position -- in central depressant or neurolepticallyactive compounds is considered to be an undesirable side-effect and isproduced by motor disorders. Representative dibenz[b,f]oxepinderivatives produced by this invention were administeredintraperitoneally to rats. The animals are considered to be catalepticwhen the homolateral extremities remain in a crossed position for atleast 10 seconds. The number of cataleptic animals is noted every 30minutes for 6 hours. The ED₅₀ is the dose at which 50% of the animalsshow catalepsy.

    ______________________________________                                        RESULTS:                                                                      Derivative        ED.sub.50 mg/kg.                                            ______________________________________                                        D                 4                                                           F                 30                                                          G                 50                                                          H                 >30                                                         Chlorpromazine     6                                                          ______________________________________                                    

From the foregoing Table, it will be noted that derivatives D, F and Gpossess only about one half to about one eighth of the undesiredcataleptic side-effect of chlorpromazine and that derivative H possessesless than one fifth of the undesired cataleptic side-effect ofchlorpromazine.

IV. Toxicity

The following values for acute toxicity in the mouse show that thetested derivatives are significantly less toxic than chlorpromazine. Thefigures relate to a duration of activity over a period of 24 hours:

    ______________________________________                                        Derivative       LD.sub.50 mg/kg.p.o.                                         ______________________________________                                        A                900                                                          B                375                                                          C                900                                                          D                750                                                          E                900                                                          F                450                                                          G                450                                                          H                1500                                                         Chlorpromazine   200                                                          ______________________________________                                    

The dibenz[b,f]oxepin derivatives provided by the present invention canbe used as medicaments, for example, in the form of pharmaceuticalpreparations which contain them in association with a compatiblepharmaceutical carrier. Such a carrier can be an organic or inorganicinert carrier material suitable for enteral, for example, oral, orparenteral administration, for example, water, gelatin, lactose, starch,magnesium stearate, talc, vegetable oils, gum arabic,polyalkyleneglycols or the like. The pharmaceutical preparations can bemade up in solid form, for example, as tablets, dragees, suppositoriesor capsules, or in liquid form, for example, as solutions, suspensionsor emulsions. The pharmaceutical preparations may be sterilized and/ormay contain adjuvants such as preserving, stabilizing, wetting oremulsifying agents, salts for varying the osmotic pressure or buffers.They may also contain other therapeutically valuable substances.

Pharmaceutical dosage forms can contain about 1 mg. to 200 mg. of acompound of formula I or of its pharmaceutically acceptable acidaddition salt. Oral dosages can comprise from about 0.1 mg/kg. per dayto about 7.5 mg/kg. per day. Parenteral dosages can comprise from about0.01 mg/kg. per day to about 0.75 mg/kg. per day. However, the foregoingranges can be varied upwards or downwards according to the individualrequirements.

The following Examples further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise specified.

EXAMPLE 1 Preparation of3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone

14.5 G. of1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-piperazine arestirred at reflux for 3 hours together with 13.4 g. of3-(2-chloroethyl)-2-oxazolidinone, 4.9 g. of sodium carbonate and 0.6 g.of sodium iodide in 80 ml. of n-butanol. Then, the solvent is evaporatedunder vacuo and the residue is partitioned between water and chloroform.The aqueous phase is extracted two additional times with chloroform. Thechloroform solutions are washed with water and with sodium chloridesolution, dried over sodium sulfate and evaporated. The residue is takenup in a small amount of ether, whereby3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone,having a melting point of 175°-176° crystallizes out. Thedihydrochloride (crystallized from ethanol/ether) melts at 183° (withdecomposition).

The 1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-piperazineused as the starting material can be prepared as follows:

20 G. of 5-methyl-anthranilic acid are suspended in 200 ml. of 3-Nhydrochloric acid at 0° C. A solution of 10 g. of sodium nitrite and 20ml. of water is added dropwise thereto with stirring and the mixture isfurther stirred for 25 minutes at 0° C. A solution of 26.5 g. ofpotassium iodide, 30 ml. of 3-N hydrochloric acid and 30 ml. of water isthen added dropwise at 5°-10° C. The mixture is stirred for anadditional 30 minutes at room temperature and for 2 hours at reflux. Themixture is cooled and sodium thiosulfate is added until the solution isyellow (5 g.). The crystalline 2-iodo-5-methyl-benzoic acid obtained isremoved by filtration under vacuum and washed neutral with water. Thecrude acid is dissolved in ether, washed well with sodium thiosulfatesolution and water, dried over sodium sulfate and evaporated, and thereare obtained light-brown crystals having a melting point of 100°-112° C.

393 G. of 2-iodo-5-methyl-benzoic acid in 150 ml. of nitrobenzene areheated to 145° C. 138 G. of potassium carbonate are added thereto insmall portions with stirring. Subsequently, 156 ml. of 4-methyl-phenoland 276 g. of potassium carbonate are added. To the resulting mixture, 3g. of copper powder are carefully added, and the mixture is subsequentlystirred at 165° C. for 20 minutes. After cooling, 1.25 liters of waterare added to the mixture which is then extracted twice with ether. Theaqueous phase is acidified with hydrochloric acid and extracted twicewith ether. The ethereal solutions are washed with water, dried oversodium sulfate and concentrated in vacuo. The residue (brown crystals)is recrystallized from 1100 ml. of methanol and 700 ml. of water, andthere is obtained 2-(4-methylphenoxy)-5-methyl-benzoic acid, which afterrepeated recrystallization from methanol/water, melts at 113°-115° C.

A solution of 121 g. of 2-(4-methyl-phenoxy)-5-methyl-benzoic acid in600 ml. of tetrahydrofuran is slowly added dropwise, with cooling in anicebath, to 420 ml. of a 70% solution of sodiumdihydro-bis(1-methoxyethoxy)aluminate in benzene and stirred for anadditional hour at room temperature. To the obtained clear solution, 800ml. of 20% aqueous sodium hydroxide solution are carefully addeddropwise. Then, the organic phase is separated. The aqueous phase isextracted three additional times with ether. The organic extracts arewashed with saturated sodium chloride solution and the latter dried oversodium sulfate. After evaporation of the ether, there is obtained2-(4-methylphenoxy)-5-methyl-benzyl alcohol as an oil.

36.5 Ml. of thionyl chloride are added dropwise at 10°-15° C. withstirring and cooling with ice to a solution of 110 g. of2-(4-methyl-phenoxy)-5-methylbenzyl alcohol in 78 ml. of pyridine. Themixture is stirred for an additional 1 hour at 10° C. and then dilutedwith 200 ml. of benzene. Then, 200 ml. of water are carefully addeddropwise with ice-cooling. The aqueous phase is separated and theorganic phase washed successively with dilute hydrochloric acid, waterand saturated sodium bicarbonate solution. The aqueous phases are eachextracted once more with benzene. The combined benzene extracts aredried over sodium sulfate and evaporated to dryness in vacuo and thereis obtained 3-chloromethyl-4-(4-methyl-phenoxy)-toluene as an oil.

A solution of 108 g. of 3-chloromethyl-4-(4-methyl-phenoxy)-toluene in70 ml. of dimethylsulfoxide is added dropwise at 20°-25° C. to asuspension of 23 g. of sodium cyanide in 35 ml. of dimethylsulfoxide.The mixture is subsequently stirred for 4 hours at 36° C., then dilutedwith 1 liter of water and extracted three times with benzene. Thebenzene extracts are washed three times with water, then dried oversodium sulfate and evaporated in vacuo, and there is obtained crude2-(4-methyl-phenoxy)-5-methyl-phenylacetonitrile as a brown oil.

A solution of 95 g. of crude2-(4-methyl-phenoxy)-5-methyl-phenylacetonitrile in 500 ml. of ethanolis treated with a solution of 67 g. of potassium hydroxide in 120 ml. ofwater and heated to reflux for 5 hours. Then, the ethanol is evaporatedin vacuo and the residue diluted with 500 ml. of water. The resultingmixture is extracted twice with ether. The ethereal extracts areextracted twice with sodium bicarbonate solution. The combined aqueoussolutions are acidified and extracted three times with ether. Theethereal extracts are washed with saturated sodium chloride solution,dried over sodium sulfate and evaporated in vacuo, and there is obtained2-(4-methyl-phenoxy)-5-methyl-phenylacetic acid which, afterrecrystallization from methanol/water, melts at 101°-104° C.

200 G. of polyphosphoric acid are mixed with 49.5 g. of2-(4-methylphenoxy)-5-methyl-phenylacetic acid at 100° C. and stirred atthis temperature for 45 minutes. The mixture is cooled, ice is added andthe mixture is extracted three times with ether. The ethereal extractsare washed successively with water, saturated sodium bicarbonatesolution and saturated sodium chloride solution, dried over sodiumsulfate and evaporated to dryness in vacuo. The residue is distilled(boiling point 140° C./0.1 Torr), and there is obtained10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-one which crystallizesfrom methanol; melting point 62°-62.5° C.

A solution of 11.35 ml. of titanium (IV) chloride in 135 ml. of benzeneis added dropwise with stirring and cooling at 20°-25° C. to a solutionof 30 g. of 10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-one and 80ml. of N-ethoxycarbonylpiperazine in 300 ml. of benzene. Then, themixture is stirred for 4 hours at reflux and cooled. The cooled mixtureis poured into a solution of 12 g. of sodium bicarbonate in 300 ml. ofwater. The precipitated titanium dioxide is removed by filtration andwashed well with benzene. The filtrate is washed four additional timeswith water. The aqueous phases are extracted again with benzene. Thecombined benzene extracts are dried over sodium sulfate and evaporatedin vacuo, and there is obtained4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acidethyl ester as an oil.

48.6 G. of4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acidethyl ester are dissolved in 750 ml. of glacial acetic acid. 18.9 G. ofsodium borohydride are added in small portions within 20 minutes withstirring and cooling in such a manner that the temperature does notexceed 25° C. The mixture is stirred for an additional 30 minutes at 25°C. and then the glacial acetic acid is removed by distillation in vacuo.The residue is partitioned between chloroform and aqueous sodiumhydroxide solution. The organic phase is separated and washed withwater. The aqueous phases are extracted two additional times withchloroform. The combined chloroform extracts are dried over sodiumsulfate, evaporated in vacuo, and there is obtained crude4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester as an oil.

22.0 G. of4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester and 22 g. of potassium hydroxide are stirred in 320 ml.of ethyleneglycol and 1.5 ml. of water for 90 minutes at 160° C. Aftercooling, the mixture is diluted with 1.3 liters of water and extractedthree times with ether. The ethereal extracts are washed twice withsaturated sodium chloride solution, dried over sodium sulfate,evaporated in vacuo, and there is obtained crude1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-piperazine as anoil.

EXAMPLE 2 Preparation of3-[2-{4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazino}-ethyl]-2-oxazolidinone

18 G. of1-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-piperazineare stirred at reflux for 3 hours together with 17.2 g. of3-(2-chloroethyl)-2-oxazolidinone, 6.0 g. of sodium carbonate and 0.8 g.of sodium iodide in 100 ml. of butanol. Then, the solvent is evaporatedunder reduced pressure and the residue partitioned between water andchloroform. The organic phase is washed with water, dried over sodiumsulfate and evaporated under reduced pressure. The residue iscrystallized by the addition of ether, removed by filtration, and thereis obtained3-[2-{4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazino}-ethyl]-2-oxazolidinonehaving a melting point of 145°-147° C. after recrystallization fromethanol. The monohydrochloride melts at 229°-230° C. (withdecomposition).

The1-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-piperazine(an oil) used as the starting material is prepared from2-iodo-5-methyl-benzoic acid and 4-fluoro-phenol in a manner analogousto that described in Example 1, via the following intermediates:

2-(4-fluoro-phenoxy)-5-methyl-benzoic acid having a melting point of127°-128° C.;

2-(4-fluoro-phenoxy)-5-methyl-benzyl alcohol (liquid; boiling point140°-145° C./0.15 Torr);

3-chloromethyl-4-(4-fluoro-phenoxy)-toluene (oil);

2-(4-fluoro-phenoxy)-5-methyl-phenylacetonitrile (oil);

2-(4-fluoro-phenoxy)-5-methyl-phenylacetic acid having a melting pointof 116°-119° C.;

8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-one, having amelting point of 75°-76° C.;

4-[8-fluoro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester, having a melting point of 106°-108.5° C.;

4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester having a melting point of 92°-96° C.

EXAMPLE 3 Preparation of3-[2-{4-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone

1-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazineis reacted with 3-(2-chloro-ethyl)-2-oxazolidinone in the mannerdescribed in Example 1, and there is obtained3-[2-{4-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinoneas an oil. The maleate, prepared in acetone, melts at 180°-182° C.

The1-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazineused as the starting material can be prepared as follows:

448 G. of 4-fluoro-phenol and 742 g. of 2-chloro-5-nitro-benzaldehydeare added to a solution of 184 g. of sodium hydroxide in 7.4 liters ofwater. The mixture is then left to cool to room temperature. Theprecipitate is removed by filtration, washed carefully with water, andthere is obtained 2-(4-fluoro-phenoxy)-5-nitro-benzaldehyde, having amelting point of 125°-126° C.

183.4 G. of 2-(4-fluoro-phenoxy)-5-nitro-benzaldehyde are stirred atreflux for 20 minutes together with 71 g. of potassium bicarbonate and82 g. of acetylglycine in 395 ml. of acetic anhydride. Then, there areadded successively 1.62 liters of glacial acetic acid, 870 ml. of waterand 675 ml. of concentrated hydrochloric acid, and the mixture isstirred for 5 hours at reflux. The resulting mixture is cooled and 1.2liters of water are added. The mixture is extracted with 3.1 liters ofmethylene chloride in 3 portions. The methylene chloride solutions arewashed twice with 2 liters of water each time and subsequently extractedwith a solution of 250 g. of sodium carbonate in 4.5 liters of water.The obtained bicarbonate solutions are acidified with hydrochloric acidand extracted with ethyl acetate. The ethyl acetate solutions are driedover sodium sulfate and evaporated in vacuo. The crystalline residue isboiled out with 400 ml. of benzene. The crystals are removed byfiltration and there is obtained2-(4-fluoro-phenoxy)-5-nitro-phenylpyruvic acid having a melting pointof 142°-143° C. By concentration of the filtrate, there is obtained anadditional amount of this compound.

560 Ml. of a 10% aqueous solution of hydrogen peroxide are addeddropwise at 0° over a period of 75 minutes to a solution of 142 g. of2-(4-fluoro-phenoxy)-5-nitro-phenylpyruvic acid in 2.23 liters of 10%sodium hydroxide solution cooled to 0° C. The mixture is subsequentlystirred for 3 hours at 25° C. and then acidified with 500 ml. ofconcentrated hydrochloric acid with cooling. This mixture is extractedtwice with methylene chloride. The methylene chloride solutions arewashed with water, dried over sodium sulfate and concentrated in vacuo.The residue is crystallized from benzene/hexane, and there is obtained2-(4-fluorophenoxy)-5-nitro-phenylacetic acid having a melting point of129°-130° C.

125 G. of 2-(4-fluoro-phenoxy)-5-nitro-phenylacetic acid are stirred in586 g. of polyphosphoric acid for 2 hours at 100° C. Then, the mixtureis treated with ice and extracted with 6 liters of ethyl acetate. In sodoing, a portion of the resulting8-fluoro-10,11-dihydro-2-nitro-dibenz[b,f]oxepin-10-one remainsundissolved and is removed by filtration. The ethyl acetate solution iswashed with water, sodium bicarbonate solution and water, dried oversodium sulfate, concentrated and8-fluoro-10,11-dihydro-2-nitro-dibenz[b,f]oxepin-10-one, having amelting point of 159°-160° C. crystallizes out.

95 G. of 8-fluoro-10,11-dihydro-2-nitro-dibenz[b,f]oxepin-10-one in 1300ml. of ethanol and 2000 ml. of ethyl acetate are hydrogenated in thepresence of 0.65 g. of platinum dioxide. The solution is filtered clear.Upon concentration,2-amino-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-one crystallizesout; melting point 161°-162° C. (after recrystallization frombenzene/hexane).

A solution of 3.6 g. of sodium nitrite in 12 ml. of water is addeddropwise at 0°-5° C. over a period of 5 minutes to a solution of 10 g.of 2-amino-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-2-one in 73 ml. of2-N aqueous methanesulfonic acid solution cooled to 0° C. The mixture issubsequently stirred for an additional 5 minutes at 0°-5° C. Theresulting diazonium salt solution is poured into a mixture of 170 ml. ofethyl acetate at about 20° C. and a solution of 13.0 g. of copper (I)chloride in 155 ml. of concentrated hydrochloric acid, and the resultingmixture is stirred at this temperature for an additional 10 minutes. Thephases are separated and the ethyl acetate solution is washed severaltimes with saturated sodium chloride solution. Then, the ethyl acetatephase is dried over sodium sulfate and evaporated in vacuo. The residueis dissolved in benzene and filtered through 31 g. of silica gel. Thebenzene eluates are evaporated in vacuo, the residue crystallized fromisopropanol, and there is obtained2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-one, having amelting point of 91°-92° C.

2-Chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-one is convertedinto the desired1-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine(an oil) in the same manner as described in Example 1, via the followingintermediates:

4-[2-chloro-8-fluoro-dibenz[b,f]oxepin-10-yl]-piperazinecarboxylic acidethyl ester having a melting point of 129°-130° C.;

4-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazinecarboxylicacid ethyl ester having a melting point of 115°-116° C.

EXAMPLE 4 Preparation of3-[2-{4-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonedihydrochloride

1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine isreacted with 3-(2-chloro-ethyl)-2-oxazolidinone in the manner describedin Example 1, and there is obtained3-[2-{4-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonedihydrochloride having a melting point of 187°-188° C. (withdecomposition).

The 1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine(melting point 120°-122° C.) used as the starting material can beprepared from 5-chloro-2-iodo-benzoic acid and 4-chloro-phenol in themanner described in Example 1, via the following intermediates:

2-(4-chloro-phenoxy)-5-chloro-benzoic acid having a melting point of132°-134° C.;

2-(4-chloro-phenoxy)-5-chloro-benzyl alcohol (oil);

1-chloro-3-chloromethyl-4-(4-chloro-phenoxy)-benzene (oil);

2-(4-chloro-phenoxy)-5-chloro-phenylacetonitrile (oil);

2-(4-chloro-phenoxy-5-chloro-phenylacetic acid having a melting point of113°-115° C.;

2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-one having a meltingpoint of 118°-119° C.;

4-[2,8-dichloro-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acidethyl ester having a melting point of 130°-132° C.;

4-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester having a melting point of 129°-131° C.

EXAMPLE 5 Preparation of3-[3-{4-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propyl]-2-oxazolidinone

8.1 G. of1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazineare stirred at reflux for 18 hours together with 5.25 g. of3-(3-chloropropyl)-2-oxazolidinone, 2.7 g. of sodium carbonate and 0.4g. of sodium iodide in 40 ml. of butanol. Then, the solvent isevaporated under reduced pressure, and the residue partitioned betweenchloroform and water. The aqueous phase is separated and extracted twoadditional times with chloroform. The chloroform solutions are washedwith aqueous sodium chloride solution, dried over sodium sulfate andevaporated under reduced pressure. The residue is dissolved in benzeneand chromatographed over 200 g. of silica gel. Impurities are firsteluted with benzene. Then, using benzene/methanol (19:1), there iseluted3-[3-{4-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propyl]-2-oxazolidinoneas an oily substance. This is converted, in acetone with maleic acid, tothe 3-[3-{4-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propyl]-2-oxazolidinone-(1:2)-maleatehaving a melting point of 149°-151° C.

The1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazineused as the starting material can be prepared as follows:

150 G. of 4-methoxy-anthranilic acid are suspended in 1 liters of waterand 80 ml. of concentrated hydrochloride acid at 0° C. To thissuspension is added dropwise over a period of 30 minutes, with stirringat 0°-5° C., a solution of 62 g. of sodium nitrite in 130 ml. of water.The resulting diazonium salt solution is stirred for an additional 15minutes at 0°-5° C. A solution of 164 g. of potassium iodide in 700 ml.of 5-N sulfuric acid is subsequently added dropwise at 3°-6° C. over aperiod of 45 minutes. The mixture is stirred at room temperature for 30minutes and subsequently slowly heated to reflux. After boiling for 2hours at reflux, the mixture is cooled to room temperature. Theseparated brown crystals are removed by filtration and washed neutralwith water. The filter cake is dried under reduced pressure and there isobtained 2-iodo- 4-methoxy-benzoic acid as brown crystals which melt at174° C. Then, the 2-iodo-4-methoxy-benzoic acid is converted in themanner described in Example 1 to give the desired starting material,1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazine,in the form of an oil. The following intermediates are obtained:

4-methoxy-2-(4-methyl-phenoxy)-benzoic acid having a melting point of156°-157° C.;

4-methoxy-2-(4-methyl-phenoxy)-benzyl alcohol (oil);

1-chloromethyl-4-methoxy-2-(4-methyl-phenoxy)-benzene (oil);

4-methoxy-2-(4-methyl-phenoxy)-phenylacetonitrile (oil);

4-methoxy-2-(4-methyl-phenoxy)-phenylacetic acid (crystals);

10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-one (oil);

4-[3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester (oil);

4-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester (oil).

EXAMPLE 6 Preparation of3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone

8.5 G. of 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazineare stirred at reflux for 4 hours together with 8.1 g. of3-(2-chloro-ethyl)-2-oxazolidinone, 2.95 g. of sodium carbonate and 0.4g. of sodium iodide in 50 ml. of butanol. Then, the solvent isevaporated under reduced pressure and the residue partitioned betweenwater and chloroform. The organic phase is washed with water, dried oversodium sulfate and evaporated under reduced pressure. The residue isrecrystallized from methanol, and there is obtained3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonehaving a melting point of 159°-160° C. The maleate, prepared in acetone,melts at 175°-177° C. (with decomposition), The dihydrochloride hydrate,prepared in ethanol, melts at 179°-181° C. (with decomposition).

The 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine usedas the starting material can be prepared as follows:

52.5 G. of 10,11-dihydro-2-nitro-dibenz[b,f]oxepin-10-one are suspendedin 900 ml. of ethyl acetate and 450 ml. of ethanol and hydrogenated inthe presence of 300 mg. of platinum oxide at room temperature and normalpressure. The catalyst is removed by filtration, the filtrate evaporatedin vacuo. The residue is crystallized from benzene/hexane, and there isobtained 2-amino-10,11-dihydro-dibenz[b,f]oxepin-10-one having a meltingpoint of 116°-117° C.

26.4 G. of 2-amino-10,11-dihydro-dibenz[b,f]oxepin-10-one are dissolvedin 230 ml. of 2-N aqueous methanesulfonic acid. The mixture is cooled to0° C. There is added dropwise thereto over a period of 7 minutes asolution of 10.7 g. of sodium nitrite in 37.5 ml. of water in such amanner that the temperature does not exceed 5° C. The mixture is stirredfor an additional 5 minutes at 5° C. Then, this solution of thediazonium methanesulfonate is poured into a mixture of 500 ml. of ethylacetate and a solution of 37.5 g. of copper (I) chloride in 450 ml. ofconcentrated hydrochloric acid. The resulting mixture is stirred for anadditional 10 minutes at room temperature and the phases are thenseparated. The ethyl acetate solution is washed several times withsaturated aqueous sodium chloride solution, dried over sodium sulfateand evaporated in vacuo. The residue is dissolved in benzene andchromatographed over 400 g. of silica gel. Upon elution with benzene,there is obtained a substance which is crystallized from a small amountof isopropanol and there is obtained2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-one having a melting pointof 60°-61° C.

The desired starting material,1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine having amelting point of 85°-87° C., can be prepared from2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-one in the manner describedin Example 1, via the following intermediates:

4-[2-chloro-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethylester having a melting point of 139°-141° C.;

4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester having a melting point of 90°-92° C.

EXAMPLE 7

In an analogous manner to that described in Example 6,

from 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine and1-(2-chloro-ethyl)-2-pyrrolidinone, there is obtained1-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-pyrrolidinonehaving a melting point of 120°-121° C. [the dihydrochloride, prepared inethanol, melts at 222°-223° C. (with decomposition)];

from 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine and1-(2-chloro-ethyl)-2-piperidone, there is obtained1-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-piperidone[the dihydrochloride, prepared in ethanol, melts at 220°-222° C. (withdecomposition)];

from 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine and1-(2-chloro-ethyl)-3-methyl-imidazolidinone, there is obtained1-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-3-methyl-2-imidazolidinone,having a melting point of 119°-121° C. [the hydrochloride, prepared inwater, melts at 200°-202° C. (with decomposition)]; and

from1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazineand 3-(2-chloro-ethyl)-2-oxazolidinone, there is obtained3-[2-{4-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinoneas an oil [the dihydrochloride, prepared in ethanol, melts at 183°-186°C. (with decomposition)].

EXAMPLE 8 Preparation of3-[2-{4-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone

In an analogous manner to that described in Example 6, from1-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine and3-(2-chloro-ethyl)-2-oxazolidinone, there is obtained3-[2-{4-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonehaving a melting point of 150°-152° C. The dihydrochloride, prepared inethanol, melts at 175°-176° C.

The 1-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine used asthe starting material can be prepared as follows:

In an analogous manner to that described in Example 6, 30 g. of2-amino-10,11-dihydro-dibenz[b,f]oxepin-10-one are diazotized with 12 g.of sodium nitrite is methanesulfonic acid solution. The solutionobtained is poured into a mixture of 540 ml. of ethyl acetate and asolution of 57.2 g. of copper (I) bromide in 666 ml. of 48% hydrobromicacid. After 10 minutes, the mixture is worked-up in the same manner asdescribed in Example 6, and there is obtained2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-one having a melting point of53°-54° C. The product is reacted further in an analogous manner to thatdescribed in Example 1 to give the desired starting material,1-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine having amelting point of 93°-94° C. The following intermediates are obtained:

4-[2-bromo-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethylester having a melting point of 168°-170° C.;

4-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester having a melting point of 94°-95° C.

EXAMPLE 9

In an analogous manner to that described in Example 5, from1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine and3-chloro-1-propanol, there is obtained3-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-1-propanolas an oil. The dihydrochloride, prepared in ethanol, melts at 206°-207°C. (with decomposition).

EXAMPLE 10 Preparation of the palmitic acid ester of3-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-1-propanol

0.8 G. of3-[4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-1-propanolare dissolved in 5 ml. of pyridine. A solution of 0.6 g. of palmiticacid chloride in 2 ml. of benzene is added dropwise thereto with coolingand the mixture stirred for 20 hours at room temperature. The solvent isthen evaporated under reduced pressure and the residue dissolved inbenzene. The solution is chromatographed over 30 g. of silica gel.Elution is carried out first with benzene and subsequently withbenzene/methanol (99:1). The palmitic acid ester of3-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-1-propanolis eluted with benzene/methanol (97.3). This ester is obtained as an oilwhich is converted in acetone with maleic acid to the crystallinemaleate having a melting point of 103°-105° C. (with decomposition).

EXAMPLE 11 Preparation of the hydrochloride of3-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propionicacid nitrile

10 G. of 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazineare heated in 2.3 ml. of acrylic acid nitrile for 4 hours at 90° C.Then, the excess acrylic acid nitrile is evaporated under reducedpressure. The residue is reacted in ethanol with 1 equivalent ofhydrogen chloride. The hydrochloride of3-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propionicacid nitrile is removed by filtration and recrystallized from ethanol;melting point 187°-189° C. (with decomposition).

EXAMPLE 12 Preparation of4-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-2-butyn-1-olhydrochloride

6 G. of 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazineare dissolved in 65 ml. of ethanol. Subsequently, there are addedsuccessively 2.7 g. of sodium carbonate, 0.27 g. of sodium iodide. Then,a solution of 2.4 g. of 4-chloro-2-butyn-1-ol in 15 ml. of ethanol isadded dropwise. The mixture is stirred for 16 hours at room temperatureand thereafter for 3.5 hours at 40° C. The ethanol is then evaporatedunder reduced pressure and the residue partitioned between water andchloroform. The phases are separated, the aqueous solution is extractedwith water and the chloroform extracts are washed with water. Thesolvent is evaporated, the residue dissolved in benzene andchromatographed over 140 g. of silica gel. Elution is carried out firstwith benzene. The4-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-2-butyn-1-olis eluted with benzene/methanol (99:1), which is obtained as an oil andis converted to the hydrochloride using the calculated amount ofhydrogen chloride in ethanol. The hydrochloride crystallizes by theaddition of ether; melting point 194°-195° C. (with decomposition).

EXAMPLE 13 Preparation of1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-(2-(propynyl)-piperazine

2.87 G. of sodium carbonate are added to a solution of 7.6 g. of1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine in 76ml. of ethanol. Then, a solution of 1.9 ml. of propargyl bromide in 15ml. of ethanol is added dropwise with stirring. The mixture is stirredfor 20 hours at room temperature and the solvent is then evaporatedunder reduced pressure. The residue is partitioned between water andchloroform. The phases are separated. The aqueous solution is extractedagain with chloroform. The chloroform solutions are washed with water,dried over sodium sulfate and evaporated under reduced pressure. Theresidue is crystallized using diisopropyl ether, and there is obtained1-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-(2-propynyl)-piperazinehaving a melting point of 105°-107° C. The dihydrochloride, prepared inethanol, melts at 213°-215° C. (with decomposition).

EXAMPLE 14 Preparation of1-[2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-methylpiperazinedihydrochloride

6.15 G. of sodium borohydride are added in small portions over a periodof 15 minutes to a solution of 12.3 g. of1-[2-fluoro-dibenzo[b,f]oxepin-10-yl]-4-methyl-piperazine in 185 ml. ofglacial acetic acid with cooling in such a manner that the temperaturedoes not exceed 25° C. The mixture is stirred for an additional 1 hourat room temperature and the acetic acid is then evaporated in vacuo. Theresidue is partitioned between 3-N sodium hydroxide solution andchloroform. The aqueous phase is separated and extracted again withchloroform. The chloroform extracts are washed three time with water,dried over sodium sulfate, evaporated in vacuo, and there is obtained1-[2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazineas a crystalline residue. The dihydrochloride, prepared in ethanol,melts at 240°-241° C. (with decomposition).

In a manner analogous to that described in the preceding paragraph, from1-[3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine,there is obtained1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine.The dihydrochloride, prepared in methanol/ether, melts at 190°-193° C.

Similarly, there is obtained

from3-[2-{4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonethe compound3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone;melting point 175°-176° C.; melting point of the dihydrochloride 183° C.(with decomposition);

from3-[2-{4-[8-fluoro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonethe compound3-[2-{4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazino}-ethyl]-2-oxazolidinone;melting point 145°-147° C.; melting point of the monohydrochloride229°-230° C. (with decomposition);

from3-[2-{4-[2-chloro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonethe compound3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone;melting point 159°-160° C.; melting point of the dihydrochloride hydrate179°-181° C. (with decomposition);

from 3-{4-[2-chloro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propionicacid nitrile the compound3-{4-[2-chloro-10,11-dihydro-dibenz[b,f]-oxepin-10-yl]-1-piperazinyl}-propionicacid nitrile; melting point 187°-189° C. (with decomposition).

The 1-[2-fluoro-10,11-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine usedas the starting material in the first paragraph of this Example can beprepared as follows:

10,11-Dihydro-2-nitro-dibenz[b,f]oxepin-10-one is hydrogenated in themanner described in Example 6 to give2-amino-10,11-dihydro-dibenz[b,f]oxepin-10-one having a melting point of116°-117° C.

33.75 G. of 2-amino-10,11-dihydro-dibenz[b,f]oxepin-10-one are dissolvedin 375 ml. of 2-N aqueous methanesulfonic acid and the solution iscooled to 0° C. A solution of 13.5 g. of sodium nitrite in 45 ml. ofwater is added dropwise at -2° C. to 0° C. within 4 minutes withstirring and cooling. The mixture is stirred at 0° C. for an additional5 minutes and then 75 ml. of 4.3-M aqueous sodium tetrafluoroboratesolution are added. After 30 minutes, the precipitated diazoniumtetrafluoroborate is removed by filtration, washed with methanol andether and carefully dried over phosphorus pentoxide.

30 G. of the foregoing diazonium tetrafluoroborate are heated from theside with a gas flame in a flask flushed with a nitrogen stream. As soonas decomposition begins (at about 140° C.), the heating is stopped andthe exothermal reaction is allowed to spread over the entire mass. Then,the mixture is heated to 190° C. for an additional 13 minutes. Aftercooling, the mixture is taken up in benzene. The insoluble fractions areremoved by filtration and the filtrate is chromatographed over 300 g. ofsilica gel. Elution with benzene yields crude2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-one, which is distilled(boiling point 85°-89° C./0.03 Torr.) and then melts at 63°-64° C.

A solution of 6.44 g. of titanium (IV) chloride in 25 ml. of benzene isadded drowpwise over a period of 15 minutes with cooling to a solutionof 9.12 g. of 2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-one and 18 g.of 1-methyl-piperazine in 100 ml. of benzene in such a manner that thetemperature does not exceed 25° C. The mixture is subsequently stirredfor 4 hours at reflux. The resulting mixture is cooled and poured into asolution of 10 g. of sodium bicarbonate in 100 ml. of water. Theprecipitated titanium dioxide is removed by filtration and washedcarefully with benzene and chloroform. The benzene solution and thechloroform solution are washed four times with water, combined, driedover sodium sulfate, evaporated in vacuo, and there is obtained crude,crystalline 1-[2-fluoro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine.

EXAMPLE 15 Preparation of1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-methylpiperazinedihydrochloride

In an analogous manner to that described in Example 14, from1-[2-chloro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine there isobtained1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine.The dihydrochloride, prepared in ethanol, melts at 238°-240° C. (withdecomposition).

The 1-[2-chloro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine having amelting point of 119°-120° C. [maleate: melting point 200°-202° C. (withdecomposition)]used as the starting material can be prepared in ananalogous manner to that described in Example 14 from2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-one and 1-methyl-piperazine.

EXAMPLE 16 Preparation of1-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazinedihydrochloride

15 G. of4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester are dissolved in 15 ml. of benzene. With stirring andcooling, 39 ml. of a 70% solution of sodiumdihydro-bis(2-methoxyethoxy)-aluminate in benzene are added dropwise ata temperature of 20°-30° C. Then, the mixture is heated to 60° C. for 1hour, again cooled and treated at 10°-15° C. with 60 ml. of 20% sodiumhydroxide solution. The phases are separated. The aqueous phase isextracted two additional times with benzene. The benzene solutions arewashed several times with saturated sodium chloride solution, dried oversodium sulfate and evaporated in vacuo. The residue is converted intothe dihydrochloride with ethanolic hydrochloric acid, and there isobtained1-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazinedihydrochloride which, after recrystallization from methanol/ether,melts at 235°-238° C. (with decomposition).

EXAMPLE 17 Preparation of1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazinedihydrochloride

4-[10,11-Dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester is reacted with sodiumdihydro-bis(2-methoxyethoxy)aluminate in the manner described in Example16, and there is obtained1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazinewhich is isolated as the dihydrochloride having a melting point of197°-198° C. (with decomposition).

EXAMPLE 18 Preparation of1-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazinedihydrochloride

4-[2-Chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylicacid ethyl ester is reacted with sodiumdihydro-bis(2-methoxyethoxy)aluminate in an analogous manner to thatdescribed in Example 16, and there is obtained1-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-methylpiperazinewhich is isolated as the dihydrochloride having a melting point of 250°C. (with decomposition).

EXAMPLE 19 Preparation of1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-4-(2-propynyl)-piperazinedihydrochloride

3.8 G. of sodium carbonate are added to a solution of 10 g. of1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazinein 55 ml. of butanol and then a solution of 2.5 ml. of propargyl bromidein 20 ml. of butanol is added dropwise. Then, the mixture is stirred for20 hours at room temperature and the solvent is removed by distillationunder reduced pressure. After working-up in an analogous manner to thatdescribed in Example 13, there is isolated crude1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-4-(2-propynyl)-piperazinein the form of an oil. The dihydrochloride, prepared in ethanol andrecrystallized from methanol/ether, melts at 210°-212° C. (withdecomposition).

EXAMPLE 20 Preparation of10,11-dihydro-8-methyl-10-(4-methyl-1-piperazinyl)-dibenz[b,f]oxepin-3-oldihydrobromide

4.0 G. of4-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-1-methyl-piperazineare dissolved in 600 ml. of methylene chloride, treated with a solutionof 8.9 g. of boron tribromide in 90 ml. of methylene chloride andstirred at room temperature for 20 hours. The residue is taken up in 150ml. of methanol, boiled at reflux for 30 minutes with active carbon,filtered, concentrated to about 70 ml., treated with ether untilturbidity sets in, and there is obtained crystalline10,11-dihydro-8-methyl-10-(4-methyl-1-piperazinyl)-dibenz[b,f]oxepin-3-oldihydrobromide having a melting point of 176° C. (with decomposition).

EXAMPLE 21 Preparation of1-[3-chloro-10,11-dihydro-7-trifluoromethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine

11.9 G. of1-[3-chloro-7-trifluoromethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazinewas reduced with sodium borohydride in glacial acetic acid in a manneranalogous to that described in Example 14, and there is obtained crude1-[3-chloro-10,11-dihydro-7-trifluoromethyl-dibenz[b,f]oxepin-10-yl]-4-methylpiperazinewhich is recrystallized from isopropanol and melts at 110° C. Thedihydrochloride, prepared in ethanol, melts at 219°-222° C. (withdecomposition).

The1-[3-chloro-7-trifluoromethyl-dibenz[b,f]oxepin-10-yl]-4-methylpiperazineused as the starting material can be prepared as follows:

In a manner analogous to that described in Example 1,4-chloro-2-iodobenzoic acid is reacted with 3-trifluoromethyl-phenol,and there is obtained 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoicacid having a melting point of 146° C.

136 G. of 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid are boiledat reflux for 2.5 hours in a mixture of 1000 ml. of methanol and 100 ml.of concentrated sulfuric acid. After concentration of the mixture undervacuum, the residue is poured on to ice and extracted with benzene. Thebenzene extracts are washed with water, aqueous sodium bicarbonatesolution and again with water. After evaporation of the benzene, thereis obtained 4-chloro-2-(3-trifluoromethylphenoxy)-benzoic acid methylester in the form of an oil.

A solution of 103 g. of 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoicacid methyl ester in 400 ml. of tetrahydrofuran is added dropwise atreflux over a period of 30 minutes to a solution of 16.2 g. of lithiumborohydride in 280 ml. of absolute tetrahydrofuran. The mixture is thencooled to 0° C. and slowly added dropwise to 400 ml. of 3-N aqueoushydrochloric acid. After the addition of 500 ml. of water, the mixtureis extracted twice with ether. After evaporation of the ether, there isobtained 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzyl alcohol in theform of an oil.

Starting from the foregoing4-chloro-2-(3-trifluoromethyl-phenoxy)-benzyl alcohol there areobtained, in a manner analogous to that described in Example 1, thefollowing intermediates:

4-chloro-2-(3-trifluoromethyl-phenoxy)-benzyl chloride (oil);

4-chloro-2-(3-trifluoromethyl-phenoxy)-phenylacetonitrile (oil);

4-chloro-2-(3-trifluoromethyl-phenoxy)-phenylacetic acid having amelting point of 80° C.;

3-chloro-10,11-dihydro-7-trifluoromethyl-dibenz[b,f]oxepin-10-one havinga melting point of 108° C.

The last-named intermediate is reached with 1-methylpiperazine in thesame manner as described in Example 14 to give the desired startingmaterial,1-[3-chloro-7-trifluoromethyl-dibenz[b,f]oxepin-10-yl]-4-methylpiperazine,having a melting point of 170° C.

EXAMPLE 22 Preparation of1-[2-{4-[10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-piperidonedihydrochloride

A solution of 3 g. of10-chloro-10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin and 5.73g. of 1-[2-(1-piperazinyl)-ethyl]-2-piperidone in 18 ml. of chloroformis heated at reflux for 20 hours. The solvent is removed in vacuo. Theresidue is partitioned between benzene and 10% aqueous sodium carbonatesolution. The benzene solution is extracted with dilute hydrochloricacid. The acid-aqueous solution is made alkaline with sodium bicarbonateand extracted with benzene. The benzene extract is washed several timeswith water, dried, evaporated in vacuo, and there is obtained1-[2-{4-[10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-piperidone.The dihydrochloride is prepared in ethanol by the addition of an excessof alcoholic hydrogen chloride. By the addition of ether, there areobtained crystals having a melting point of 183°-185° C. (withdecomposition). By re-dissolving the dihydrochloride in water, there isobtained the monohydrochloride having a melting point of 117°-120° C.

The 10-chloro-10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin usedas the starting material is prepared as follows:

In a manner analogous to that described in Example 1, the followingintermediates are prepared:

5-methyl-2-(4-methylthio-phenoxy)-benzoic acid having a melting point of124°-125° C. (from 2-iodo-5-methyl-benzoic acid and4-methylthio-phenol);

5-methyl-2-(4-methylthio-phenoxy)-benzyl alcohol (oil);

3-chloromethyl-4-(4-methylthio-phenoxy)-toluene (oil);

5-methyl-2-(4-methylthio-phenoxy)-phenylacetonitrile (oil);

5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid.

The foregoing acid is obtained in the form of a crude oil and ispurified as follows:

47 g. of crude 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid aredissolved in 170 ml. of methanol. 19 Ml. of concentrated sulfuric acidare added dropwise with stirring and the mixture is subsequently heatedat reflux for 3.5 hours. After cooling, the mixture is diluted withwater and extracted several times with benzene. The benzene extracts arewashed with water, sodium bicarbonate solution and again with water.After evaporation of the solvent, there remains a residue which ischromatographed on 400 g. of silica gel. By elution with benzene, thereis obtained 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid methylester, which ester is dissolved in 73 ml. of methanol, treated with 18.8g. of potassium hydroxide and 73 ml. of water and subsequently heated atreflux for 1 hour. Thereafter, the methanol is removed in vacuo and theresidue acidified with hydrochloric acid. The mixture is extracted withbenzene, the benzene extract washed with water and concentrated invacuo. The residue is crystallized from cyclohexane, and there isobtained 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid having amelting point of 81°-83° C.

By treatment of the foregoing acid with polyphosphoric acid in a manneranalogous to that described in Example 1, there is obtained10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-one having amelting point of 102°-103° C.

8.9 G. of 10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-oneare suspended in 65 ml. of ethanol and treated with a solution of 1.25g. of sodium borohydride in 4.3 ml. of water. The mixture is stirred for2 hours at room temperature. Then, 20 ml. of methanol are added theretoand the resulting mixture is heated at reflux for 15 minutes.Thereafter, the methanol and ethanol are removed by evaporation invacuo. The residue is extracted with chloroform, the chloroform extractsare washed with water, dried and evaporated in vacuo. The residue iscrystallized from diisopropyl ether, and there is obtained10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin-10-ol having amelting point of 67°-69° C.

7.5 G. of 10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin-10-oneare dissolved in 75 ml. of benzene. 7.5 G. of anhydrous calcium chlorideare added thereto and the mixture is saturated with hydrogen chloride.Then, the resulting mixture is stirred at room temperature for 16 hoursand filtered. The filtrate is evaporated in vacuo and there is obtained10-chloro-10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin.

EXAMPLE 23 Preparation of1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-allyl-piperazinedihydrochloride

A solution of 8.3 g. of1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]piperazine in 90ml. of ethanol is treated with 3.55 g. of sodium carbonate. Then, asolution of 2.3 ml. of allyl bromide in 19 ml. of ethanol is addeddropwise with stirring over a period of 10 minutes. The resultingmixture is stirred for an additional 100 minutes and then the solvent isevaporated in vacuo. The residue is partitioned between water andchloroform. The chloroform phase is evaporated in vacuo. The residue isdissolved in benzene and chromatographed over 200 g. of silica gel.Impurities are first removed by elution with benzene. The oily1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-allyl-piperazineis eluted with a mixture of 98% benzene and 2% methanol. Thedihydrochloride, prepared in ethanol, melts at 219°-221° C. (withdecomposition).

EXAMPLE 24 Preparation of1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazinedihydrochloride

0.8 G. of 10-chloro-10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin and0.58 g. of 1-methyl-piperazine are dissolved in 4 ml. of chloroform andheated at reflux for 21 hours. Then, the chloroform is evaporated invacuo. The residue is partitioned between benzene and aqueous sodiumcarbonate solution. The benzene solution is extracted with dilutehydrochloric acid. The hydrochloric acid extract is made alkaline withsodium carbonate and extracted with benzene. Thereafter, the benzeneextract is washed several times with water, dried over sodium sulfate,evaporated in vacuo, and there is obtained1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine,the dihydrochloride of which melts at 197°-198° C. (with decomposition).

In a manner analogous to that described in the preceding paragraph, byreacting 10-chloro-10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin with3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone there is obtained3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonehaving a melting point of 175°-176° C.

Similarly, there is obtained

from 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin and3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone the compound3-[2-{4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazino}-ethyl]-2-oxazolidinone;melting point 145°-147° C.; melting point of the monohydrochloride229°-230° C. (with decomposition);

from 2,10-dichloro-10,11-dihydro-dibenz[b,f]oxepin and3-[(1-piperazinyl)-ethyl]-2-oxazolidinone the compound3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone;melting point 159°-160° C.; melting point of the dihydrochloride hydrate179°-181° C. (with decomposition);

from 2,10-dichloro-10,11-dihydro-dibenz[b,f]oxepin and3-(1-piperazinyl)-propionic acid nitrile the compound3-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propionicacid nitrile; melting point of the dihydrochloride 187°-189° C. (withdecomposition).

The 10-chloro-10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin used as thestarting material can be prepared in a manner analogous to thatdescribed in Example 22 from10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-one by reduction to form10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-ol having a meltingpoint of 73.5°-74° C. and subsequent treatment with hydrogen chloride inthe presence of calcium chloride. Analogous procedures apply to themanufacture of10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin and2,10-dichloro-10,11-dihydro-dibenz[b,f]oxepin.

The following Examples illustrate pharmaceutical preparations containingthe representative dibenz[b,f]oxepin derivatives of the invention:

EXAMPLE A

    ______________________________________                                        Tablets                                                                                        Per Tablet                                                   ______________________________________                                        3-[2-{4-[10,11-Dihydro-2,8-                                                   dimethyl-dibenz[b,f]oxepin-                                                   10-yl]-1-piperazinyl}-ethyl]-2-                                               oxazolidinone      100 mg.                                                    Lactose            202 mg.                                                    Maize Starch        80 mg.                                                    Hydrolyzed maize starch                                                                           20 mg.                                                    Calcium stearate    8 mg.                                                     Total Weight       410 mg.                                                    ______________________________________                                    

The3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone,lactose, maize starch and hydrolyzed maize starch are mixed together andgranulated with water to form a viscous paste. This paste is passedthrough a sieve and subsequently dried at 45° C. overnight. The driedgranulate is passed through a sieve and, thereafter, mixed with thecalcium stearate. The mixture obtained is pressed into tablets eachweighing 410 mg. and having a diameter of about 10 mm.

EXAMPLE B

    ______________________________________                                        Tablets                                                                                            Per Tablet                                               ______________________________________                                        3-[2-{4-[10,11-Dihydro-2,8-                                                   dimethyl-dibenz[b,f]oxepin-10-yl]-                                            1-piperazinyl}-ethyl]-2-oxazolidinone                                                                25.0 mg.                                               Lactose                114.0 mg.                                              Maize starch           50.0 mg.                                               Gelatinized maize starch                                                                              8.0 mg.                                               Calcium stearate        3.0 mg.                                               Total Weight           200.0 mg.                                              ______________________________________                                    

The3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone,lactose, maize starch and gelatinized maize starch are intimately mixedwith one another. The mixture is passed through a comminuting machineand moistened with water to give a thick paste. The moist mass is passedthrough a sieve. The moist granulate is thereafter dried at 45° C. Thedried granulate is thoroughly mixed with the calcium stearate. Then, thegranulate is pressed to tablets each weighing 200 mg. and having adiamter of ca. 8 mm.

EXAMPLE C

    ______________________________________                                        Tablets                                                                                            Per Tablet                                               ______________________________________                                        3-[2-{4-[10,11-Dihydro-2,8-                                                   dimethyl-dibenz[b,f]oxepin-10-yl]-                                            1-piperazinyl}-ethyl]-2-oxazolidinone                                         dihydrochloride        14.5 mg.                                               Lactose                124.5 mg.                                              Maize starch           50.0 mg.                                               Gelatinized maize starch                                                                              8.0 mg.                                               Calcium stearate        3.0 mg.                                               Total Weight           200.0 mg.                                              ______________________________________                                    

The3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonedihydrochloride, lactose, maize starch and gelatinized maize starch areintimately mixed with one another. The mixture is passed through acomminuting machine and subsequently moistened with water to give athick paste. The moist mass is passed through a sieve. The moistgranulate is dried at 45° C. The dried granulate is thoroughly mixedwith the calcium stearate. Thereafter, the granulate is pressed intotablets each weighing 200 mg. and having a diameter of ca. 8 mm.

EXAMPLE D

    ______________________________________                                        Tablets                                                                                         Per Tablet                                                  ______________________________________                                        3-[2-{4-[10,11-Dihydro-2,8-                                                   dimethyl-dibenz[b,f]oxepin-10-                                                yl]-1-piperazinyl}-ethyl]-2-                                                  oxazolidinone       25.00 mg.                                                 Lactose             110.00 mg.                                                Maize starch        61.00 mg.                                                 Talc                 3.40 mg.                                                 Magnesium stearate   0.60 mg.                                                 Total Weight        200.00 mg.                                                ______________________________________                                    

The ingredients are intimately mixed with one another and pressed totablets each weighing 200 mg. The tablets are subsequently coated withethylcellulose and Carbowax.

EXAMPLE E

    ______________________________________                                        Capsules                                                                                           Per Capsule                                              ______________________________________                                        3-[2-{4-[10,11-Dihydro-2,8-                                                   dimethyl-dibenz[b,f]oxepin-10-yl]-                                            1-piperazinyl}-ethyl]-2-oxazolidinone                                         hydrochloride          29.0 mg.                                               Lactose                156.0 mg.                                              Maize starch           30.0 mg.                                               Talc                    5.0 mg.                                               Total content          220.0 mg.                                              ______________________________________                                    

The3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonehydrochloride, lactose and maize starch are intimately mixed with oneanother and passed through a comminuting machine. The mixture is thenthoroughly mixed with the talc and filled into hard-shell gelatincapsules.

EXAMPLE F

    ______________________________________                                        Capsules                                                                                        Per Capsule                                                 ______________________________________                                        3-[2-{4-[10,11-Dihydro-2,8-                                                   dimethyl-dibenz[b,f]oxepin-10-                                                yl]-1-piperazinyl}-ethyl]-2-                                                  oxazolidinone       25.5 mg.                                                  Lactose             159.5 mg.                                                 Maize starch        30.0 mg.                                                  Talc                 5.0 mg.                                                  Total content       220.0 mg.                                                 ______________________________________                                    

The3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone,lactose and maize starch are intimately mixed with one another andpassed through a comminuting machine. The mixture is thoroughly mixedwith the talc and thereafter filled into hard-shell gelatin capsules.

EXAMPLE G

    ______________________________________                                        Parenteral Formulation                                                        Each 1 ml. ampul contains the following ingredients:                          3-[2-{4-[10,11-Dihydro-2,8-dimethyl-                                          dibenz[b,f] oxepin-10-yl]-1-piperazinyl}-                                                                10.20 mg.                                          ethyl]-2-oxazolidinone     (2% excess)                                        Methanesulfonic acid for injection purposes                                                               2.22 mg.                                          Glucose for injection purposes                                                                           40.0 mg.                                           Water for injection purposes q.s. ad                                                                      1 ml.                                             ______________________________________                                    

22.2 G. of methanesulfonic acid for injection purposes, 102 g. of3-[2-{4-[10,11-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinoneand 400 g. of glucose are successively dissolved in 8000 ml. of waterfor injection purposes in a glass vessel with stirring at roomtemperature. Then, water for injection purposes is added to provide atotal volume of 10,000 ml. The solution is either filtered sterile andfilled into colorless ampuls which are gassed with nitrogen and sealedor filled into colorless ampuls which are gassed with nitrogen, sealedand then sterilized with a stream of steam or autoclaved at 120° C.

EXAMPLE H

In place of the active ingredients used in Examples A-G, there can alsobe used other dibenz[b,f]oxepin derivatives of the invention, forexample:

3-[2-{4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinoneor the dihydrochloride thereof;

3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinoneor the maleate thereof;

3-{3-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-propionicacid nitrile or the hydrochloride thereof.

We claim:
 1. A compound of the formula ##STR19## wherein R is a group ofthe formula ##STR20## wherein X is oxygen, lower alkylimino ormethylene, Y is ethylene or propylene; m is zero; one of R₁ and R₂ ishydrogen and the other is halogen, lower alkyl, or lower alkoxy; and oneof R₃ and R₄ is hydrogen and the other is hydrogen, halogen, loweralkyl, or lower alkylthio,or a pharmaceutically acceptable acid additionsalt thereof.
 2. A compound in accordance with claim 1, wherein R is##STR21## or a pharmaceutically acceptable acid addition salt thereof.3. A compound in accordance with claim 2,3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone,or a pharmaceutically acceptable acid addition salt thereof.
 4. Acompound in accordance with claim 2,3-[2-{4-[8-fluoro-10,11-dihydro-2-methyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone,or a pharmaceutically acceptable acid addition salt thereof.
 5. Acompound in accordance with claim 2,3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinoneor a pharmaceutically acceptable acid addition salt thereof.
 6. Inaccordance with claim 1,3-[2-{4-[2,8-dichloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonedihydrochloride.
 7. In accordance with claim 1,3-[2-{4-[2-chloro-8-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinonemaleate.